EA019206B1 - Пиразиновые соединения в качестве ингибиторов фосфодиэстеразы 10 - Google Patents
Пиразиновые соединения в качестве ингибиторов фосфодиэстеразы 10 Download PDFInfo
- Publication number
- EA019206B1 EA019206B1 EA201100748A EA201100748A EA019206B1 EA 019206 B1 EA019206 B1 EA 019206B1 EA 201100748 A EA201100748 A EA 201100748A EA 201100748 A EA201100748 A EA 201100748A EA 019206 B1 EA019206 B1 EA 019206B1
- Authority
- EA
- Eurasian Patent Office
- Prior art keywords
- benzo
- pyrazin
- phenyl
- yloxy
- imidazol
- Prior art date
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- 150000003216 pyrazines Chemical class 0.000 title abstract description 3
- 239000003112 inhibitor Substances 0.000 title description 22
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 title description 3
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 115
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 60
- 201000010099 disease Diseases 0.000 claims abstract description 45
- 238000000034 method Methods 0.000 claims abstract description 26
- 201000000980 schizophrenia Diseases 0.000 claims abstract description 19
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 claims abstract description 15
- 208000020925 Bipolar disease Diseases 0.000 claims abstract description 13
- -1 oxaspiro [3.5] nonyl Chemical group 0.000 claims description 651
- 125000005605 benzo group Chemical group 0.000 claims description 298
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 claims description 282
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 271
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 claims description 246
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 199
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 151
- RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical compound NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 claims description 147
- 229920006395 saturated elastomer Polymers 0.000 claims description 107
- WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 claims description 100
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 57
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 40
- 229910052799 carbon Inorganic materials 0.000 claims description 39
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical group C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 claims description 39
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 38
- 125000004429 atom Chemical group 0.000 claims description 37
- 229910052757 nitrogen Inorganic materials 0.000 claims description 35
- 150000003839 salts Chemical class 0.000 claims description 34
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 29
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 claims description 28
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 27
- 229910052794 bromium Inorganic materials 0.000 claims description 24
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 20
- DEPDDPLQZYCHOH-UHFFFAOYSA-N 1h-imidazol-2-amine Chemical compound NC1=NC=CN1 DEPDDPLQZYCHOH-UHFFFAOYSA-N 0.000 claims description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 19
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 18
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 17
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 claims description 16
- 206010012289 Dementia Diseases 0.000 claims description 15
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 15
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 15
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 14
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims description 12
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 12
- NIMQYXHSYCEJLU-UHFFFAOYSA-N 4-(3-morpholin-4-ylpyrazin-2-yl)oxybenzaldehyde Chemical compound C1=CC(C=O)=CC=C1OC1=NC=CN=C1N1CCOCC1 NIMQYXHSYCEJLU-UHFFFAOYSA-N 0.000 claims description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
- 229910052700 potassium Inorganic materials 0.000 claims description 11
- 230000001404 mediated effect Effects 0.000 claims description 10
- FTMRNDSFXBWBBN-UHFFFAOYSA-N O1CCC(CC1)C=1C(=NC=CN1)OC1=CC=C(C=C1)C=O Chemical compound O1CCC(CC1)C=1C(=NC=CN1)OC1=CC=C(C=C1)C=O FTMRNDSFXBWBBN-UHFFFAOYSA-N 0.000 claims description 9
- 208000018737 Parkinson disease Diseases 0.000 claims description 9
- 125000004122 cyclic group Chemical group 0.000 claims description 9
- FWFSEYBSWVRWGL-UHFFFAOYSA-N cyclohex-2-enone Chemical compound O=C1CCCC=C1 FWFSEYBSWVRWGL-UHFFFAOYSA-N 0.000 claims description 9
- 125000005843 halogen group Chemical group 0.000 claims description 9
- IIKFXOLJMNWWCH-UHFFFAOYSA-N piperidine-1,4-dicarboxylic acid Chemical compound OC(=O)C1CCN(C(O)=O)CC1 IIKFXOLJMNWWCH-UHFFFAOYSA-N 0.000 claims description 9
- DATJETPTDKFEEF-UHFFFAOYSA-N pyrrolidine-3-carbonitrile Chemical compound N#CC1CCNC1 DATJETPTDKFEEF-UHFFFAOYSA-N 0.000 claims description 9
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 8
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 8
- 208000028017 Psychotic disease Diseases 0.000 claims description 8
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 8
- 239000013256 coordination polymer Substances 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
- JAEIBKXSIXOLOL-UHFFFAOYSA-N pyrrolidin-1-ium-3-carboxylate Chemical compound OC(=O)C1CCNC1 JAEIBKXSIXOLOL-UHFFFAOYSA-N 0.000 claims description 8
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 7
- OBFWKHFOQNLCHV-UHFFFAOYSA-N COC1=NC=CC=C1C=1C(=NC=CN1)OC1=CC=C(C=C1)C=O Chemical compound COC1=NC=CC=C1C=1C(=NC=CN1)OC1=CC=C(C=C1)C=O OBFWKHFOQNLCHV-UHFFFAOYSA-N 0.000 claims description 7
- XJLSEXAGTJCILF-UHFFFAOYSA-N nipecotic acid Chemical compound OC(=O)C1CCCNC1 XJLSEXAGTJCILF-UHFFFAOYSA-N 0.000 claims description 7
- 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 claims description 6
- VAHJIEDUYQRDKF-UHFFFAOYSA-N CC1=NC=CC=C1C=1C(=NC=CN1)OC1=CC=C(C=C1)C=O Chemical compound CC1=NC=CC=C1C=1C(=NC=CN1)OC1=CC=C(C=C1)C=O VAHJIEDUYQRDKF-UHFFFAOYSA-N 0.000 claims description 6
- NYXHUSNUGHZSKK-UHFFFAOYSA-N COC1CCN(CC1)C=1C(=NC=CN1)OC1=CC=C(C=C1)C=O Chemical compound COC1CCN(CC1)C=1C(=NC=CN1)OC1=CC=C(C=C1)C=O NYXHUSNUGHZSKK-UHFFFAOYSA-N 0.000 claims description 6
- GFZWHAAOIVMHOI-UHFFFAOYSA-N azetidine-3-carboxylic acid Chemical compound OC(=O)C1CNC1 GFZWHAAOIVMHOI-UHFFFAOYSA-N 0.000 claims description 6
- 229910052796 boron Inorganic materials 0.000 claims description 6
- PQANGXXSEABURG-UHFFFAOYSA-N cyclohex-2-en-1-ol Chemical compound OC1CCCC=C1 PQANGXXSEABURG-UHFFFAOYSA-N 0.000 claims description 6
- 125000001188 haloalkyl group Chemical group 0.000 claims description 6
- FSDNTQSJGHSJBG-UHFFFAOYSA-N piperidine-4-carbonitrile Chemical compound N#CC1CCNCC1 FSDNTQSJGHSJBG-UHFFFAOYSA-N 0.000 claims description 6
- NLGQVZJXELIMRV-UHFFFAOYSA-N COCC1N(CCC1)C=1C(=NC=CN1)OC1=CC=C(C=C1)C=O Chemical compound COCC1N(CCC1)C=1C(=NC=CN1)OC1=CC=C(C=C1)C=O NLGQVZJXELIMRV-UHFFFAOYSA-N 0.000 claims description 5
- 206010008748 Chorea Diseases 0.000 claims description 5
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- 208000012601 choreatic disease Diseases 0.000 claims description 5
- RLZJFTOYCVIYLE-UHFFFAOYSA-N oxane-4-carbonitrile Chemical compound N#CC1CCOCC1 RLZJFTOYCVIYLE-UHFFFAOYSA-N 0.000 claims description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
- FLUZXGUPVIQIBW-UHFFFAOYSA-N N1CCC(CC1)C=1C(=NC=CN1)OC1=CC=C(C=C1)C=O Chemical compound N1CCC(CC1)C=1C(=NC=CN1)OC1=CC=C(C=C1)C=O FLUZXGUPVIQIBW-UHFFFAOYSA-N 0.000 claims description 4
- LWEHAYWSXSNTAN-UHFFFAOYSA-N OC1CC(CCC1)C=1C(=NC=CN1)OC1=CC=C(C=C1)C=O Chemical compound OC1CC(CCC1)C=1C(=NC=CN1)OC1=CC=C(C=C1)C=O LWEHAYWSXSNTAN-UHFFFAOYSA-N 0.000 claims description 4
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- 206010043118 Tardive Dyskinesia Diseases 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 230000006735 deficit Effects 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 claims description 4
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims description 3
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- WXGATHRIMCDRGO-UHFFFAOYSA-N 4-(3-pyridin-4-ylpyrazin-2-yl)oxybenzaldehyde Chemical compound N1=CC=C(C=C1)C=1C(=NC=CN=1)OC1=CC=C(C=C1)C=O WXGATHRIMCDRGO-UHFFFAOYSA-N 0.000 claims description 3
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Classifications
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- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
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- Bioinformatics & Cheminformatics (AREA)
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- Pain & Pain Management (AREA)
- Endocrinology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (3)
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US11456708P | 2008-11-14 | 2008-11-14 | |
US16621209P | 2009-04-02 | 2009-04-02 | |
PCT/US2009/064637 WO2010057121A1 (en) | 2008-11-14 | 2009-11-16 | Pyrazine compounds as phosphodiesterase 10 inhibitors |
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EA201100748A1 EA201100748A1 (ru) | 2011-10-31 |
EA019206B1 true EA019206B1 (ru) | 2014-01-30 |
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EA201100748A EA019206B1 (ru) | 2008-11-14 | 2009-11-16 | Пиразиновые соединения в качестве ингибиторов фосфодиэстеразы 10 |
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Cited By (1)
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RU2632900C2 (ru) * | 2010-11-19 | 2017-10-11 | Лиганд Фармасьютикалс Инкорпорейтед | Гетероциклические амины и их применение |
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